DESCRIPTION: (Adapted from the application) The normal low heart rate and respiratory sinus arrhythmia present in healthy animals and humans is determined primarily by the activity of parasympathetic cardiac neurons in the brain stem. However, cardiac vagal activity and respiratory sinus arrhythmia are diminished and unresponsive in many disease states, including hypertension, heart failure, and sudden cardiac death. Work completed during the previous funding period of this grant has shown cardia vagal neurons do not possess pacemaker-like activity, and the normal tonic vagal activity to the heart must be strongly determined and regulated by synaptic pathways. Surprisingly, however, despite the physiological importance of cardiac vagal activity, little is known about the crucial synaptic innervation of brain stem cardiac vagal neurons. This proposal is a logical extension of the results obtained during the previous funding period and is based in part upon both the PI's in vitro and in vivo preliminary observations that cholinergic neurons and pathways in the central nervous system play a major role in the control of cardiac vagal activity. This project will directly identify, at the cellular and intact system levels, the cholinergic neurons and mechanisms by which acetylcholine can modulate the sensitivity of the baroreceptor reflex and mediate cardiorespiratory rhythms. Specifically, the PI will: (1) test the hypothesis that destruction of cholinergic neurons that project to the nucleus ambiguous inhibits the baroreflex control and respiratory modulation of cardiac vagal activity; (2) test the hypothesis that the glutamatergic transmission from NTS neurons to identified cardiac vagal neurons is increased by acetylcholine; and (3) characterize the electrophysiological properties of NTS neurons that project to cardiac vagal neurons. The anticipated results will provide information fundamental to understanding the basis and mechanisms of cardiac vagal activity and cardio-respiratory rhythms that originate in the medulla, and will also suggest which receptors and processes could be altered in diseases of the cardiorespiratory system.